A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD) resulting in an atypical form of alpha-ketoglutarate dehydrogenase deficiency

The alpha-ketoglutarate dehydrogenase complex (KGDC) catalyses the decarboxylation of alpha-ketoglutarate into succinyl-coenzyme A in the Krebs cycle. This enzymatic complex is made up of three subunits (E1, encoded by PDHA1; E2, encoded by DLST; and E3, encoded by DLD). The E3 subunit is common to two other enzymatic complexes, namely pyruvate dehydrogenase complex (PDC) and branched-chain ketoacid dehydrogenase complex (BCKDC). KGDC deficiency is a rare autosomal recessive disorder, most often presenting with severe encephalopathy and hyperlactatemia with neonatal onset. We found a KGDC deficiency in cultured skin fibroblasts from three siblings born to consanguinous parents. E3 subunit activity was shown to be deficient (20% of control values), despite the absence of usual clinical clues to E3 deficiency, i.e. accumulation of pyruvate and branched-chain amino acids in plasma and branched-chain alpha-ketoacids in urine. RT-PCR of E3 mRNA from the three patients, followed by sequencing, revealed an homozygous c.1444A>G substitution located in E3 exon 13, predictive of a p.R482G (or R447G in the processed gene product) substitution in a highly conserved domain of the protein. Only eleven E3 mutations have been reported so far. The only other case of E3 deficiency without clinical or biochemical evidences of PDC and BCKDC deficiencies has been ascribed to a c.1436A>T (p.D479V; or D444V in the processed gene product) mutation, very close to the mutation reported herein. Since c.1444A>G (p.R482G; or R447G in the processed gene product) and c.1436A>T (p.D479V; or D444V in the processed gene product) lie within the interface domain of E3 with E2 (KGDC and BCKDC) or the E3-binding protein (PDC), our data suggest that interaction of E3 with these other subunits differs in some extent among KGDC, PDC, and BCKDC.     

Radiologic case study. Secondary hyperparathyroidism,osteomalacia with a pseudofracture,and amyloid deposition

The advancement of medical management of chronic renal failure has helped eliminate secondary hyperparathyroidism and osteomalacia. However, if a patient is recalcitrant, florid forms of both conditions can develop. Secondary amyloidosis is poorly understood but occurs in patients who are on long-term dialysis. As the survival rates for patients on long-term dialysis improve, it will be seen more frequently.     

Cancer chemotherapy and heterocyclic compounds

The search for pharmacological approaches to neoplastic disease has made some impressive gains started after 1940 when the antileukemic activity of nitrogen mustard was discovered during world war II. It is generally accepted that neoplastic transformation is related to genes alteration or oncogene activation, so the progress in the development of the new drugs for treatment of malignant diseases has been rapid, both in revealing pathobiology of the diseases and discovery of new drugs. In addition attempts have been made to define optimal combinations, treatment strategies and patient support measures. Cancer chemotherapy is now of established value and a highly specialized field. Among the modifications to the family of antitumor compounds, heterocyclic organic compounds have been extensively applied by many groups in order to modify the reactivity profile. Pyrrole, pyrimidine, indole, quinoline and purine are few classes of heterocycles which showed interesting cytotoxicity profiles. The updated material related to these modifications has been rationalized and ordered, in order to offer an overview of the argument.     

Synthesis of 4-aryl-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2-one/thione-5-one derivatives and evaluation as antibacterials

A novel, ecofriendly, one pot solvent free method for the synthesis of 4-aryl-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2-one/thione-5-one derivatives is described which devoids the use of any organic solvents and auxiliaries. All the synthesized compounds were screened for their in vitro antibacterial activity against standard strains of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa.     

The effect of spirituality and religious attendance on the relationship between psychological distress and negative life events

Purpose

The aim of this study was to assess the effect of religious attendance and spirituality on the relationship between negative life events and psychological distress.

Methods

This was a cross-sectional study of 1,071 community dwelling adults from East Baltimore, Maryland who participated in the fourth (2004–2005) wave of the Baltimore Epidemiologic Catchment Area study. The 20-item General Health Questionnaire (GHQ-20) was used to measure psychological distress. Multiple regression models were used to assess the association between negative life events and distress as well as to measure the effect of religious attendance and spirituality on the association between psychological distress and negative events while adjusting for demographic variables, past distress and social support from friends and relatives.

Results

In pooled analysis, negative events were significant predictors of distress, b = 1.00, β = 0.072, p < 0.05. Religious attendance and spirituality did not affect or modify the association between negative events and distress. However, religious attendance was inversely associated with distress with higher frequency of attendance associated with lower distress after controlling for demographic and social support factors, b = ?2.10, β = ?.110, p < 0.01 for attending 1–3 times a month; b = ?2.39, β = ?0.156, p < 0.01 for attending weekly; and b = ?3.13, β = ?0.160, p < 0.001 for attending more than once per week. In stratified analysis, negative events were associated with distress for those who were low on spirituality, b = 1.23, β = 0.092, p < .05, but not for those who were high on spirituality; the association between religious attendance and decreased distress was true only for those scoring high in spirituality. Social support accounted for some of the inverse association between religious and distress.

Conclusion

Religious attendance and spirituality may play a role in how people experience and deal with difficult life situations.     

In vitro conversion of proinsulin to insulin by cathepsin B and role of C-peptide

Summary Cathepsin B, purified from isolated islets of Langerhans, when incubated with proinsulin underin vitro conditions could convert proinsulin to insulin and C-peptide, releasing free arginine and lysine. When C-peptide, prepared from rat pancreas, was added to the incubation system consisting of proinsulin and cathepsin B, it completely inhibited the conversion of proinsulin to insulin. Communication no. 2295 from the Central Drug Research Institute, Lucknow, India.